Histone Deacetylase Inhibition by Gut Microbe-Generated Short-Chain Fatty Acids Entrains Intestinal Epithelial Circadian Rhythms. Gastroenterology 2022 Nov;163(5):1377-1390.e11
Date
08/08/2022Pubmed ID
35934064Pubmed Central ID
PMC11551968DOI
10.1053/j.gastro.2022.07.051Scopus ID
2-s2.0-85140087418 (requires institutional sign-in at Scopus site) 139 CitationsAbstract
BACKGROUND & AIMS: The circadian clock orchestrates ∼24-hour oscillations of gastrointestinal epithelial structure and function that drive diurnal rhythms in gut microbiota. Here, we use experimental and computational approaches in intestinal organoids to reveal reciprocal effects of gut microbial metabolites on epithelial timekeeping by an epigenetic mechanism.
METHODS: We cultured enteroids in media supplemented with sterile supernatants from the altered Schaedler Flora (ASF), a defined murine microbiota. Circadian oscillations of bioluminescent PER2 and Bmal1 were measured in the presence or absence of individual ASF supernatants. Separately, we applied machine learning to ASF metabolomics to identify phase-shifting metabolites.
RESULTS: Sterile filtrates from 3 of 7 ASF species (ASF360 Lactobacillus intestinalis, ASF361 Ligilactobacillus murinus, and ASF502 Clostridium species) induced minimal alterations in circadian rhythms, whereas filtrates from 4 ASF species (ASF356 Clostridium species, ASF492 Eubacterium plexicaudatum, ASF500 Pseudoflavonifactor species, and ASF519 Parabacteroides goldsteinii) induced profound, concentration-dependent phase shifts. Random forest classification identified short-chain fatty acid (SCFA) (butyrate, propionate, acetate, and isovalerate) production as a discriminating feature of ASF "shifters." Experiments with SCFAs confirmed machine learning predictions, with a median phase shift of 6.2 hours in murine enteroids. Pharmacologic or botanical histone deacetylase (HDAC) inhibitors yielded similar findings. Further, mithramycin A, an inhibitor of HDAC inhibition, reduced SCFA-induced phase shifts by 20% (P < .05) and conditional knockout of HDAC3 in enteroids abrogated butyrate effects on Per2 expression. Key findings were reproducible in human Bmal1-luciferase enteroids, colonoids, and Per2-luciferase Caco-2 cells.
CONCLUSIONS: Gut microbe-generated SCFAs entrain intestinal epithelial circadian rhythms by an HDACi-dependent mechanism, with critical implications for understanding microbial and circadian network regulation of intestinal epithelial homeostasis.
Author List
Fawad JA, Luzader DH, Hanson GF, Moutinho TJ Jr, McKinney CA, Mitchell PG, Brown-Steinke K, Kumar A, Park M, Lee S, Bolick DT, Medlock GL, Zhao JY, Rosselot AE, Chou CJ, Eshleman EM, Alenghat T, Hong CI, Papin JA, Moore SRAuthor
Emily M. Eshleman PhD Assistant Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
ARNTL Transcription FactorsAnimals
Butyrates
Caco-2 Cells
Circadian Rhythm
Fatty Acids, Volatile
Gastrointestinal Microbiome
Histone Deacetylase Inhibitors
Histone Deacetylases
Humans
Luciferases
Mice
Propionates
